The photoreceptors of the retina are involved in the two basic functions of the eye: detection of light and adaptation to varying light intensities. We have found that the photoreceptors contain high levels of enzymes which catalyze cyclic nucleotide synthesis and degradation. The goal of this project is to determine the role of these enzymes and those affected by cyclic nucleotides in retinal function and disease. Our results to date indicate that cyclic GMP is synthesized and degraded more readily than is cyclic AMP in this system. Light inhibits guanylate cyclase with a half-time of several minutes, suggesting that cyclic GMP may have a role in adaptation. In the present phase of this program we will try to determine the mechanism by which cyclic nucleotides act in this system and examine the role of the cyclic nucleotides in retinal disease. Our data suggest that cyclic GMP acts in this system through activation of a cyclic nucleotide-dependent protein kinase. We will examine this further, concentrating on identification of the substrate for this enzyme. Cyclic nucleotide phosphodiesterase has been found missing from photoreceptors of mice with inherited retinal degeneration. We will examine enzymes of cyclic nucleotide metabolism in rats with a similar disease.